(beta, beta-diarylacrylyloxy)-alkylammonium salts



Patented Mar. 30, 1954 (B B-DIARYLACRYLYLOXY) -ALKYL- AMMONIUM SALTSKurt Rorig, Chicago, Ill., assignor to G. D. Searle & 00., Chicago,111., a corporation of Illinois No Drawing. Application March 25, 1952,Serial No. 278,507

12 Claims. (Cl. 260-2943) The present invention relates to a new groupof quaternary ammonium salts and, more particularly, to the(Bfi-diarylacrylyloxy)alkylammonium salts which can be represented bythe structural formula wherein Ar is an aryl radical, A is eitherhydrogen or a lower alkyl radical, X is an anion, R is an aliphatic typeradical, and NRR" is either a lower dialkylamino radical or anitrogen-containing heteromonocyclic radical.

In the foregoing structural formula Ar can be a lower aryl radical offrom 6 to 10 carbon atoms such as phenyl, tolyl, xylyl, and naphthyl.The radical A is either hydrogen or a lower alkyl radical such asmethyl, ethyl, propyl and the like. The radical Alk is a lower bivalentsaturated aliphatic hydrocarbon radical and includes such straight chainor branch chain hydrocarbon radicals as ethylene, propylene, butylene,amylene,

hexylene and polymethylene radicals such as trimethylene,tetramethylene, pentamethylene and hexamethylene.

The radical R can be a lower alkyl radical such as methyl, ethyl,propyl, butyl, amyl, and hexyl wherein the propyl, butyl, amyl and hexylradicals can be of the straight chain and branch chain type, as well asa lower aralkyl radical such as benzyl and .phenethyl. The radicals Rand R" can be lower alkyl radicals of the foregoing type. The radicalNR'R" can also be a saturated nitrogen-containing heterocyclic radicalj-attached to the radical Alk through a nitrogen ture of the anion is ofrelatively minor importance since the cation becomes associated withother anions in vivo.

The quaternary ammonium salts of this invention are valuable medicinalagents, particularly as inhibitors of autonomic nervous functions. Thesesalts inhibit the transmission of autonomic nerve impulses through bothsympathetic and parasympathetic ganglia thus .producing a chemicalequivalent of surgical sympathectomy. They are useful in the control ofgastroduodenal ulcer and other gastro-intestinal diseases associatedwith autonomic hyperactivity. In their effect on the intestines thesesalts differ from the corresponding tertiary bases and their simpleaddition salts, which have a spasmolytic efiect only at the site of theafiected organ, in that the quaternary salts prevent the nerve impulsesfrom reaching the neuro-effector junction and producing damage at theirritated target organ.

The compounds which constitute my invention can be prepared by a numberof methods. A convenient method consists in the transesterification of alower alkyl ester of the diarylacrylic acid with the correspondingdialkylaminoalkanol or N-(hydroxyalkyl)heterocycle; the resulting esteris then quaternized by treatment with the corresponding organic ester.

Another method consists in the treatment oi. the diarylacroyl halideswith alcohols of the foregoing type. Esterification can likewise beaccomplished by treatment of the afl-diarylacrylic acid with ahaloalkyldialkylamine. Still another method consists in the dehydrationwith formic acid of the hydracrylates of the type shown in theexperimental part below.

The following examples describe in detail certain of the compounds whichconstitute this invention and the methods for their production. However,this invention is not to be construed as limited thereby in spirit or inscope. It will be apparent to organic chemists that many modificationsin materials and methods may be made without departing from theinvention. In these examples temperatures are given in degreescentigrade C.), quantities are indicated in parts by weight, andpressures in millimeters (mm.) of mercury.

Example 1 A solution of 48 parts of pp-diphenylacrylic acid chloride in450 parts of benzene is treated with 18 parts offi-hydroxyethyldimethylamine. There is an immediate exothermic reactionwhich is completed by heating at reflux temperature for 5 hours. Thereaction mixture is extracted with dilute hydrochloric acid and theextract is washed with ether, rendered alkaline by addition of potassiumcarbonate and extracted with ether. This ether extract is dried overanhydrous calcium sulfate and evaporated, yielding thepedimethylaminoethyl ester of 5,,8-dipheny1acrylic acid as an oil whichis distilled at about 154-155 C. and 0.3 mm. pressure. Treatment of anether (C|H)|C=CH--C o ooHi-oH,1 (oHi Replacement of the methyl bromideby 10.5 parts of benzyl chloride yields the(afi-diphenylacrylyloxy)ethyldimethylbenzylammonium chloride in the formof small, clear prisms. This salt has the structural formula A solutionof 112 parts of 5,5-diphenylacrylic acid and 68 parts offi-chloroethyldiethylamine and 750 parts of isopropanol is heated atreflux temperature for 6 hours and concentrated to one-half of itsoriginal volume. After cooling the precipitate is collected on a filter.The hydrochloride of the B-diethylaminoethyl lie-diphenylacrylate thusobtained melts at 159-163 C. upon recrystallization from isopropanol.

235. parts of this hydrochloride are dissolved '.in ice cold water. Thesolution is rendered alkaline by addition of potassium carbonate andextracted with ether. This extract is dried over anhydrous potassiumcarbonate, filtered and evaporated. The residue is dissolved in acetone,treated with 120 parts of methyl bromide and heated. to 85 C. for 18hours. Recrystallized from chloroform and ethyl acetate, the (pp-dr-.phenylacrylyloxy) ethyldiethylmethylammonium bromide melts at about146-147 C. It has the structural formula A solution of 64 parts ofB-hydro'xyethyldi-nbutylamine and 51 parts of ethyl B,e-diphenyl-'acrylate in 300 parts of xyle'neis heated at reflux temperature. Uponaddition of 0.5 part of sodium there occurs a vigoroustransesterification reaction and the azeotropic mixture of ethanol andxylene is distilled off. The residue is washed with water, dried overanhydrous sodium sulfate and distilled. The dibutylaminoethyl ester ofdiphenylacrylic acid is obtained as a golden yellow oil distilling atabout 192-193 C. and 0.3 "mm. pressure. It forms a hydrochloride which,recrystallized from a mixture of ethanol and ether, melts at about113-114 C.

A solution of parts of'the basic ester and 10 parts of methyl bromide in80 parts of butanone is heated at 85 C. in a shielded pressure reactorfor 36 hours. After'cooling and'treat- 'ment with ether an oil separateswhich solidifies on scratching. Recrystallized from a mixture ofchloroform and ethyl acetate the (13,5diphenylacrylyloxy)ethyldibutylmethylform within 10 minutes.

4 ammonium bromide melts at about 131-132 C. It has the structuralformula 20 parts of Bfi-diphenylacrylic acid are converted to the acidchloride with 250 parts of thionyl chloride and, after removal of theexcess of the thionyl chloride, the acid chloride is taken up in benzeneand treated with one equivalent of 1-dimethylamino-2-propanol. Themixture isheated at reflux temperature for 4 hours and then treated withwater. The aqueous layer is separated, rendered alkaline by addition ofpotassium carbonate and extracted with ether. This extract is evaporatedunder vacuum to yield the fi-dimethylamino-u-methylethyl ester of[3,B-diphenylacrylic acid which distils at about 154-156" C. and 0.3 mm.pressure. Its hydrochloride melts at about 170-171" C.

A solution of 10 parts of the basic distillate and 10 parts of diethylsulfate in 100 parts of butanone is heated at 50 C. for an hour andchilled. The resulting oil, upon treatment with ether, crystallizes toform the (ap-diphenylacrylyloxy) isopropyldimethylethylammonium sulfatein the form of light yellow crystals. This salt has the structuralformula A solution of 455 parts of -hydroxypropyldiethylamine and504'parts of ethyl fifi-diphenylacrylate in 2800 -parts of xylene istreated with '7 parts of sodium metal and heated gently at refluxtemperature for minutes. The azeotropic mixture of xylene and ethanol isgradually distilled oif and replaced by xylene. The final xylenesolution is washed with Water, treated with an equal volume of ether anddried over anhydrous sodium sulfate, filtered and evaporated. The-diethylaminopropyl SLB-diphenyl- 'acrylate thus obtained is distilledat about 173-182" C. and 0.3 mm. pressure. It forms a hydrochloridewhich, recrystallized from visopropanol, melts at about l02-104 C.

A solution of'1'50 parts of the distillate in 800 parts of butanone istreated'with parts of methyl bromide at room temperature. Crystals Uponrecrystallization from a mixture of chloroform and ethyl acetate, the(dB-diphenylacrylyloxy) propyldiethylmethylammonium bromide melts atabout -112 C. This'very-hygroscopic salt has the structural Example 6 Asolution of 154 parts of a-methyl-B,B-diphenylacrylic acid, 136 parts offl-chloroethyldiethylamine and 600 parts of hot isopropanol is. heatedat reflux temperaturefor 20 hours and filtered. to remove a smallquantity of dimer. The filtrate is concentrated. by evaporation and thecrystalline precipitate'is collected on a filter, Recrystallized fromethanol and a very large quantitybf' ether,

the hydrochloride of the fi-diethylaminoethyl ester ofa-methyl-;8,p-diphenylacrylic acid is obtained which melts at about1441-145 C. An aqueous solution of the salt is rendered alkaline byaddition of potassium carbonate and extracted with ether. This etherextract is dried over anhydrous potassium carbonate, filtered and evaporated to yield the free base. parts of this base are dissolved in 100parts of butanone and treated with 12 parts of propyl iodide. Within ashort time the(a-methyl-B,c-diphenylacry1yloxy)ethyldiethylpropylammonium iodideseparates as an oil which solidifies into yellowish nee dles uponchilling. It has the structural for- Example 7 A solution of 65 parts offi,B-di(l-naphthyl)- acrylic acid (cf. Weizmann et al., Journal AmericanChem. Society, volume 70, page 1612: 1948) and 35.5 parts ofechlorobutylmorpholine in 300 parts of isopropanol is heated at refluxtemperature for 8 hours. The solution is then filtered while hot and thefiltrate is concentrated, cooled and treated with dilute hydrochloricacid. The

aqueous layer is separated, washed with ether,

decolorization. The N-(fl,fi-di-1-naphthylacryl- I yloxy) butyl N methylmorpholinium iodide is obtained in small, clear prisms which have thestructural formula A solution of 51 parts of ethyl pfi-diphenylacrylateand 51 parts of N-(B-hydroxyethyl)pyrrolidine in 320 parts of xylene istreated with 0.5 part of sodium metal. The mixture of ethanol and xyleneis distilled ofi gently and as two 130 part portions are removed theyare replaced by 85 part portions of xylene. The residue is extractedwith water, dried over anhydrous potassium carbonate, filtered anddistilled, the p-pyrrolidinoethyl ester of ,Bfi-diphenylacrylic acidbeing collected at about 183-185 C. and 0.3 mm. pressure. This baseforms a crystalline hydrochloride which melts at about 128-129 C.

Treatment of a solution of parts of the basic ester in 80 parts ofbutanone with 13 parts of methyl bromide produces separation of an oilwithin 5 minutes which crystallizes on standing at 0 C. Recrystallizedfrom a. mixture of chloroform and ethyl acetate, the N-(B,8-diphenylacrylyl0xy ethyl N methylpyrrolidinium bro- 6 mide melts atabout 149-151 C. It has the structural formula A solution of 50 parts ofN-(fi-hydroxyethyD- piperidine and 51 parts of ethylB,B-diphenylacrylate in 320 parts of xylene is treated with 0.5 parts ofsodium and heated gently to boiling temperature. The azeotropic mixtureof xylene and ethanol is distilled 01f with gradual replacement byxylene in the course of 2 hours. The residue is diluted with benzene andextracted twice with water, dried and vacuum distilled. Thec-piperidinoethyl ester of 5,3-diphenylacrylic acid is distilled atabout 194196 C. and 0.3 mm. pressure. On standing this distillatesolidifies; the base has a freezing point of about 65 C. Thehydrochloride derived therefrom melts at about 169-1'l0 C. uponrecrystallization from a mixture of ethanol and ether.

Upon treatment of a solution of 185 parts of the basic ester in 800parts of butanone with parts of methyl bromide crystals are formedwithin 10 minutes. Recrystallized from a mixture of chloroform and ethylacetate the N-(apdiphenylacrylyloxy) ethyl N methyl piperidinium bromidemelts at about 182 C. It has the structural formula Br CH2-CH2 Example10 A slurry of 49 parts of B,,Bdiphenyl-fi-hydroxy propionic acid with235 parts of isopropanol is heated at reflux temperature for 2 hourswith a 50% xylene solution of 23 parts of fi-chloroethyldimethylamine.The mixture is filtered and the isopropanol removed from the filtrateunder reduced pressure. The semi-crystalline residue is recrystallizedfrom a mixture of ethanol and ether to yield the hydrochloride of thedimethylaminoethyl ester of Bp-diphenylhydracrylic acid, melting atabout 172173 C. 168 parts of this hydrochloride are dissolved in water,rendered alkaline by addition of potassium carbonate and extracted withether. This ether extract is dried over anhydrous potassium carbonate,filtered and evaporated. The residue is taken up in butanone and 100parts of methyl bromide are bubbled in. An immediate precipitate of themethobromide forms which is collected on a filter and washed. It meltsat about 178-180 C. Preparation of the acrylates of Example 1 bydehydration of these hydracrylates is less efficient than the methodshown in Example 1.

Example 11 A mixture of 40 parts of ,3, 8-diphenyl-p-hydroxypropionicacid and 315 parts of isopropanol is stirred and heated to reflux. Afterslight cooling 22.5 parts of fi-chloroethyldiethylamine are added and inthe course of the moderately exothermic reaction the slurry turns into aclear solution. Refluxing is continued for 2 hours after which themixture is filtered hot and the isopropanol is distilled off undervacuum. Recrystallized from a mixture of ethanol and ether thehydrochloride of the fi-diethylaminoethyl ester or was 7mg-diphenylhydracrylic acid is obtained in colorless crystals meltingat'about 145-146" C.- The base is liberated by alkalinization of thehydrochloride, extraction with ether and concentration. Treatment of abutanone solution of the base with methyl bromide yields the crystallinemethobromide which melts atabout 136-138 C.

Preparation of the acrylic acid derivative of Example 2 by dehydrationof the hydracrylic acid derivative is less efiective than the methodshown in'Example 2.

I claim:

1. The quaternary ammonium salts of the cationic formula wherein AI isan aryl hydrocarbon radical of 6 tolflcarbon atoms, A is a member of theclass consisting of hydrogen and lower alkyl radicals, Alk is a loweralkylene radical separating the carboxy radical and nitrogen by at least2 carbon atoms, R is a member of the class consisting of lower alkylradicals and lower phenylalkyl radicals, and NR'R" is a member of theclass consistin of lower dialkylamino radicals, pyrrolidino radicals,piperidino radicals and morpholino radica 2. The (5,3diarylacrylyloxy)alkyltrialkylammonium salts wherein the aryl radicalsare aryl hydrocarbon radicals of 6 to 10 carbon atoms, the alkylradicals are lower alkyl radicals and the nitrogen atom and the carboxylradical are separated by a lower alkylene radical containing at least 2carbon atoms.

3. The (B,B-diphenylacrylyloxy)alkyltrialkylammonium salts wherein thealkyl radicals are lower alkyl radicals and the nitrogen atom and thecarboxyl radical are separated by a lower alkylene radical containing atleast 2 carbon atoms.

4. The (p, 3-diphenylacrylyloxy)alkyltrimethylammonium salts whereinthealkyl radical is a lower alkyl radical separating the nitrogen atomand the carboxyl radical by at least 2 carbon atoms.

5. The (flfi diphenylacrylyloxy)ethyltrimethylammonium salts.

6. The (p43- diphenylacrylyloxy)alkyldiethyb methylammonium saltswherein the alkyl radical is a lower alkyl radical separating thenitrogen atom'and the carboxyl radical by at least'2car bon atoms.

7. The (5,5 diphenylacrylyloxy) ethyldiethylmethylammonium salts.

8. The (pfl-diphenylacrylyloxwpropyldiethylmethylammonium salts. L

9. The N (5,5 diphenylacrylyloxy) alkyl-N- lower alkylpyrrolidiniumsalts wherein the nitrogen and carboxyl radicals are separated by alower alkylene radical containing at least 2 carbon atoms.

10. The N (flfi-diphenylacrylyloxy)ethyl-N- methylpyrrolidinium salts.

11. The N (pp-diphenylacrylyloxy)alkyl-N- lower alkylpiperidinium saltswherein the'nitrogen and carboxyl radicals are separated by a loweralkylene'radical containing at least 2 carbon atoms.

12. The N (5,;8-diphenylacrylyloxy)ethyl-N- methyl-piperidinium salts.

KURT RORIG.

References Cited in the file, of this patent UNITED STATES PATENTSNumber Name Date 1,817,670 Brill Aug. 4, 1 931 2,310,973 Lott Feb. 16,1943 2,475,852 Northey et a1. July 12, 1949

1. THE QUATERNARY AMMONIUM SALTS OF THE CATIONIC FORMULA